👤 Rushdia Z Yusuf

BackgroundAlthough the molecular basis of Alzheimer's disease (AD) is often studied in Caucasians, its genetic basis in Bangladesh remains elusive.ObjectiveWe explored the association between single-nucleotide variants (SNVs) of Apolipoprotein E ( Show less

Hypertriglyceridemia is a prevalent lipid disorder that considerably increases the risk of cardiovascular diseases, pancreatitis, and metabolic syndrome. Existing treatment options, including lifestyle changes and medications, often show limited effectiveness and may cause side effects. Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (APOC3), represents a novel therapeutic strategy for lowering triglyceride levels. This systematic review and meta-analysis assess the efficacy and safety of olezarsen in comparison to a placebo for managing hypertriglyceridemia. A systematic literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across databases such as PubMed, Google Scholar, and the Cochrane Library, incorporating clinical trials and conference proceedings. Studies that compared olezarsen with a placebo and reported outcomes related to triglyceride levels, APOC3, and other lipid parameters were included. Two independent reviewers conducted data extraction and quality assessment. Statistical analyses were performed using RevMan, employing risk ratios for dichotomous variables and standard mean differences for continuous variables, with a random-effects model. Three randomized controlled trials, comprising 334 participants, were included in the analysis. Olezarsen significantly lowered triglyceride levels at both 6 months (standard mean difference [SMD]: -1.69, 95% CI -2.22 to -1.17) and 12 months (SMD: -1.64, 95% CI -2.22 to -1.07). Very low-density lipoprotein (VLDL) levels also declined at 6 months (SMD: -1.95, 95% CI -2.38 to -1.51) and 12 months (SMD: -0.83, 95% CI -1.13 to -0.53). Additional lipid profile improvements included reductions in total cholesterol, non-HDL cholesterol, and apoB levels, along with increases in HDL cholesterol and apoA-1. The incidence of adverse events was similar between the olezarsen and placebo groups. Olezarsen effectively reduces triglyceride and VLDL levels while enhancing lipid profiles in patients with hypertriglyceridemia. Although serious adverse events were more frequent, the overall safety profile remains acceptable. Further long-term research is required to validate these findings and optimize treatment regimens. Show less

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder characterized by left ventricular hypertrophy and variable clinical manifestations, including asymptomatic states and sudden cardiac death (SCD). Data on its phenotype and genotype in the Indian population remain limited. We studied 113 patients diagnosed with HCM. All underwent clinical assessment, 24-h Holter monitoring, echocardiography, and cardiac MRI. Genetic testing was performed in 80 patients. Clinical and imaging features were compared between genotype-positive and genotype-negative groups. The mean age was 47 ± 10.8 years, with 82.6 % being males. Dyspnoea and chest pain were the most frequent symptoms. Obstructive HCM was seen in 70 (61.9 %) patients. Cardiac MRI showed late gadolinium enhancement >15 % in 13 (23.2 %) and apical aneurysms in 2 (3.5 %). Genetic mutations were detected in 40 (50 %) patients, with MYBPC3 (33 %) and MYH7 (26.8 %) being most common. Genotype-positive individuals more frequently had chest pain, a family history of SCD, and more severe hypertrophy. In this Indian HCM cohort, the condition predominantly affected males. Genotype-positive patients exhibited more severe hypertrophy and adverse clinical profiles, underscoring the importance of genetic screening in risk stratification. Show less

Long-term exposure to air pollution has been associated with higher risk of cardiovascular mortality. Less is known about the association of air pollution with initial development of cardiovascular disease. Herein, the association between low-level exposure to air pollutants and subclinical carotid atherosclerosis in adults without known clinical cardiovascular disease was investigated. Cross-sectional analysis within a prospective cohort study. The Canadian Alliance for Healthy Hearts and Minds Cohort Study; a pan-Canadian cohort of cohorts. Canadian adults (n = 6645) recruited between 2014-2018 from the provinces of British Columbia, Alberta, Ontario, Quebec, and Nova Scotia, were studied, for whom averages of exposures to nitrogen dioxide (NO2), ozone (O3), and fine particulate matter (PM2.5) were estimated for the years 2008-2012. Carotid vessel wall volume (CWV) measured by magnetic resonance imaging (MRI). In adjusted linear mixed models, PM2.5 was not consistently associated with CWV (per 5 μg/m3 PM2.5; adjusted estimate = -8.4 mm3; 95% Confidence Intervals (CI) -23.3 to 6.48; p = 0.27). A 5 ppb higher NO2 concentration was associated with 11.8 mm3 lower CWV (95% CI -16.2 to -7.31; p<0.0001). A 3 ppb increase in O3 was associated with 9.34 mm3 higher CWV (95% CI 4.75 to 13.92; p<0.0001). However, the coarse/insufficient O3 resolution (10 km) is a limitation. In a cohort of healthy Canadian adults there was no consistent association between PM2.5 or NO2 and increased CWV as a measure of subclinical atherosclerosis by MRI. The reasons for these inconsistent associations warrant further study. Show less

Excess adipose tissue increases other cardiovascular risk factors, which may be associated with vascular brain injury and cognitive impairment. However, the extent to which the amount and distribution of adipose tissue may be associated with lower cognitive scores, independent of its association with cardiovascular risk factors, is not well characterized. To investigate the association of adiposity on vascular brain injury and cognitive scores. A total of 9189 participants from the Canadian Alliance for Healthy Hearts and Minds (CAHHM) and the Prospective Urban Rural Epidemiological-Mind (PURE-MIND) cohort studies were included in this cross-sectional analysis. Of these adults, 9166 underwent bioelectrical impedance analysis to assess body fat (BF) percentage, and 6773 underwent magnetic resonance imaging to assess vascular brain injury and measure visceral adipose tissue (VAT) volume. Participants from CAHHM were recruited from January 1, 2014, to December 31, 2018, and PURE-MIND participants were recruited from January 1, 2010, to December 31, 2018. Both CAHHM and PURE-MIND comprise multisite, population-based cohorts. Participants from CAHHM are from Canada, and PURE-MIND participants are from Canada or Poland. Data analysis was performed from May 3 to November 24, 2021. The percentage of BF and VAT were modeled as sex-specific quartiles. Vascular brain injury was defined as high white matter hyperintensities or silent brain infarction. Multivariable mixed models were used to examine factors associated with reduced cognitive scores. Cognitive function was assessed using the Digital Symbol Substitution Test (DSST; scores range from 0 to 133, with lower scores indicating lower cognitive function) and Montreal Cognitive Assessment (scores range from 0 to 30, with a score of ≥26 denoting normal cognitive function). Reduced cognition was defined as a DSST score less than 1 SD below the mean. Cardiovascular risk was assessed using the INTERHEART Risk Score (IHRS; scores range from 0 to 48; low risk is defined as a score of 0 to 9, moderate risk as 10 to 16, and high risk as 17 or higher). A total of 9189 adults (mean [SD] age, 57.8 [8.8] years; 5179 [56.4%] women; and 1013 [11.0%] East and Southeast Asian; 295 [3.2%] South Asian; 7702 [83.8%] White European; and 179 [1.9%] other, including Black, Indigenous, mixed, and unknown ethnicity) participated in the study. Visceral adipose tissue was highly correlated with body adiposity measured by BF percentage (r = 0.76 in women; r = 0.70 in men). Cardiovascular risk factors increased with increasing BF percentage with the fourth quartile IHRS at 13.8 (95% CI, 13.5-14.0; P < .001 for trend) and with VAT with the fourth quartile IHRS at 13.3 (95% CI, 13.0-13.5; P < .001 for trend). Vascular brain injury increased with increasing BF percentage with the fourth quartile value at 8.6% (95% CI, 7.5%-9.8%; P = .007 for trend) and with increasing VAT with fourth quartile value at 7.2% (95% CI, 6.0-8.4; P = .05 for trend). Cognitive scores were lower with increasing BF percentage with the fourth quartile score of 70.9 (95% CI, 70.4-71.5; P < .001 for trend) and for VAT with the fourth quartile score of 72.8 (95% CI, 72.1-73.4; P < .001 for trend). For every 1-SD increase in BF percentage (9.2%) or VAT (36 mL), the DSST score was lower by 0.8 points (95% CI, 0.4-1.1; P < .001) for BF percentage and lower by 0.8 points (95% CI, 0.4-1.2; P < .001) for VAT, adjusted for cardiovascular risk factors and vascular brain injury. The population attributable risk for reduced DSST score for higher BF percentage was 20.5% (95% CI, 7.0%-33.2%) and for VAT was 19.6% (95% CI, 2.0%-36.0%). Higher BF percentage and VAT were not associated with Montreal Cognitive Assessment scores. In this cross-sectional study, generalized and visceral adiposity were associated with reduced cognitive scores, after adjustment for cardiovascular risk factors, educational level, and vascular brain injury. These results suggest that strategies to prevent or reduce adiposity may preserve cognitive function. Show less

A growing number of single-nucleotide polymorphisms (SNPs) have been associated with body mass index (BMI) and obesity, but whether the effects of these obesity-susceptibility loci are uniform across the BMI distribution remains unclear. We studied the effects of 37 BMI-associated SNPs in 75,230 adults of European ancestry across BMI percentiles by using conditional quantile regression (CQR) and meta-regression (MR) models. The effects of nine SNPs (24%)-rs1421085 (FTO; p = 8.69 × 10 Show less

Physical activity (PA) has been shown to reduce the impact of FTO variation and obesity genetic risk scores (GRS) on BMI. We examined this interaction using a quantitative measure of PA and two adiposity indexes in a longitudinal multi-ethnic study. We analyzed the impact of PA on the association between 14 obesity predisposing variants (analyzed independently and as a GRS) and baseline/follow-up obesity measures in the multi-ethnic prospective cohort EpiDREAM (17423 participants from six ethnic groups). PA was analyzed using basic (low-moderate-high) and quantitative measures (metabolic equivalents (METS)), while BMI and the body adiposity index (BAI) were used to measure obesity. Increased PA was associated with decreased BMI/BAI at baseline/follow-up. FTO rs1421085, CDKAL1 rs2206734, TNNl3K rs1514176, GIPR rs11671664 and the GRS were associated with obesity measures at baseline and/or follow-up. Risk alleles of three SNPs displayed nominal associations with increased (NTRK2 rs1211166, BDNF rs1401635) or decreased (NPC1 rs1805081) basic PA score independently of BMI/BAI. Both basic and quantitative PA measures attenuated the association between FTO rs1421085 risk allele and BMI/BAI at baseline and follow-up. Our results show that physical activity can blunt the genetic effect of FTO rs1421085 on adiposity by 36-75% in a longitudinal multi-ethnic cohort. Show less

Observational studies have shown a positive association between obesity (body mass index [BMI] ≥ 30 kg/m2) and depression. Around 120 obesity-associated loci have been identified, but genetic variants associated with depression remain elusive. Recently, our team reported that the fat mass and obesity-associated (FTO) gene rs9939609 obesity-risk variant is paradoxically inversely associated with the risk of depression. This finding raises the question as to whether other obesity-associated genetic variants are also associated with depression. Twenty-one obesity gene variants other than FTO were selected from a custom ∼50,000 single-nucleotide polymorphisms (SNPs) genotyping array (ITMAT-Broad-CARe array). Associations of these 21 SNPs and an unweighted genotype score with BMI and major depressive disorder (determined using the DSM-IV diagnostic criteria) were tested in 3,209 cases and 14,195 noncases, using baseline data collected from July 2001 to August 2003 from the multiethnic EpiDREAM study. Body mass index was positively associated with depression status (odds ratio [OR] = 1.02; 95% CI, 1.02-1.03 per BMI unit; P = 2.9 × 10(-12), adjusted for age, sex, and ethnicity). Six of 21 genetic variants (rs1514176 [TNN13K], rs2206734 [CDKAL1], rs11671664 [GIPR], rs2984618 [TAL1], rs3824755 [NT5C2], and rs7903146 [TCF7L2]) and the genotype score were significantly associated with BMI (1.47 × 10(-14) ≤ P ≤ .04). Of the 21 SNPs, TAL1 rs2984618 obesity-risk allele was associated with a higher risk of major depressive disorder (P = 1.79 × 10(-4), adjusted for age, sex, BMI, and ethnicity), and BDNF rs1401635 demonstrated significant ethnic-dependent association with major depressive disorder (OR = 0.88; 95% CI, 0.80-0.97; P = .01 in non-Europeans and OR = 1.11; 95% CI, 1.02-1.20; P = .02 in Europeans; Pinteraction = 2.73 × 10(-4)). The genotype score, calculated with or without FTO rs9939609, and adjusted for the same covariates, was not associated with depression status. Our data support the view that the association between obesity and major depressive disorder at the observational level may be explained, at least in part, by shared genetic factors. Show less

The glycosyltransferase gene, Ext1, is essential for heparan sulfate production. Induced deletion of Ext1 selectively in Mx1-expressing bone marrow (BM) stromal cells, a known population of skeletal stem/progenitor cells, in adult mice resulted in marked changes in hematopoietic stem and progenitor cell (HSPC) localization. HSPC egressed from BM to spleen after Ext1 deletion. This was associated with altered signaling in the stromal cells and with reduced vascular cell adhesion molecule 1 production by them. Further, pharmacologic inhibition of heparan sulfate mobilized qualitatively more potent and quantitatively more HSPC from the BM than granulocyte colony-stimulating factor alone, including in a setting of granulocyte colony-stimulating factor resistance. The reduced presence of endogenous HSPC after Ext1 deletion was associated with engraftment of transfused HSPC without any toxic conditioning of the host. Therefore, inhibiting heparan sulfate production may provide a means for avoiding the toxicities of radiation or chemotherapy in HSPC transplantation for nonmalignant conditions. Show less

Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG. Show less

Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of lipoprotein metabolism--'hyperlipoproteinemia' (HLP)--it remains largely unresolved whether any of these SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP phenotypes. To address this question, we evaluated 28 TG-associated SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls. We found that several SNPs associated with TG in normolipidemic samples, including APOA5 p.S19W and -1131T>C, TRIB1 rs17321515, TBL2 rs17145738, GCKR rs780094, GALNT2 rs4846914 and ANGPTL3 rs12130333, were significantly associated with HLP types 2B, 3, 4 and 5. The findings indicate that: (i) the TG-associated Fredrickson HLP types 2B, 3, 4 and 5 are polygenic traits; (ii) these Fredrickson HLP types share numerous genetic determinants among themselves; and (iii) genetic determinants of modest TG variation in normolipidemic population samples also underlie--to an apparently even greater degree--susceptibility to these rare HLP phenotypes. Thus, the TG-associated Fredrickson HLP types 2B, 3, 4 and 5, although historically considered to be distinct are actually complex traits sharing among them several common genetic determinants seen in GWAS of normolipidemic population samples. Show less

Recent genome-wide association studies (GWAS) have reproducibly identified loci associated with plasma triglycerides (TG), HDL cholesterol, and LDL cholesterol. We sought to replicate these findings in a multiethnic population-based cohort using the curated single nucleotide polymorphism (SNP) set found on the new Illumina cardiovascular disease (CVD) beadchip, which contains approximately 50,000 SNPs densely mapping approximately 2,100 genes, selected based on their potential role in CVD. The sample consisted of individuals with European (n = 272), South Asian (n = 330), and Chinese (n = 304) ancestry. Identity by state clustering successfully classified individuals according to self-reported ethnicities. Associations between TG and APOA5, TG and LPL, HDL and CETP, and LDL and APOE were all identified (P < 2 x 10(-6)). In 13 loci, associations with the same SNP or a proxy SNP were identified in the same direction as previously reported (P < 0.05). Assessing the cumulative number of risk-associated alleles at multiple replicated SNPs increased the proportion of explained lipoprotein variance over and above traditional variables such as age, sex, body mass index, and ethnicity. The findings indicate the potential utility of the Illumina CVD beadchip, but they underscore the need to consider meta-analysis of results from commonly studied clinical or epidemiological samples. Show less

Several known candidate gene variants are useful markers for diagnosing hyperlipoproteinemia. In an attempt to identify other useful variants, we evaluated the association of two common APOA5 single-nucleotide polymorphisms across the range of classic hyperlipoproteinemia phenotypes. We assessed plasma lipoprotein profiles and APOA5 S19W and -1131T>C genotypes in 678 adults from a single tertiary referral lipid clinic and in 373 normolipidemic controls matched for age and sex, all of European ancestry. We observed significant stepwise relationships between APOA5 minor allele carrier frequencies and plasma triglyceride quartiles. The odds ratios for hyperlipoproteinemia types 2B, 3, 4 and 5 in APOA5 S19W carriers were 3.11 (95% CI 1.63-5.95), 4.76 (2.25-10.1), 2.89 (1.17-7.18) and 6.16 (3.66-10.3), respectively. For APOA5 -1131T>C carriers, the odds ratios for these hyperlipoproteinemia subtypes were 2.23 (95% CI 1.21-4.08), 3.18 (1.55-6.52), 3.95 (1.85-8.45) and 4.24 (2.64-6.81), respectively. The overall odds ratio for the presence of either allele in lipid clinic patients was 2.58 (95% CI 1.89-3.52). A high proportion of patients with four classic hyperlipoproteinemia phenotypes are carriers of either the APOA5 S19W or -1131T>C variant or both. These two variants are robust genetic biomarkers of a range of clinical hyperlipoproteinemia phenotypes linked by hypertriglyceridemia. Show less

Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation identified in GWA studies would also be associated with severe hypertriglyceridemia (HTG). We studied 132 patients of European ancestry with severe HTG (fasting plasma TG > 10 mmol/l), who had no mutations found by resequencing of candidate genes, and 351 matched normolipidemic controls. We determined genotypes for: GALNT2 rs4846914, TBL2/MLXIPL rs17145738, TRIB1 rs17321515, ANGPTL3 rs12130333, GCKR rs780094, APOA5 rs3135506 (S19W), APOA5 rs662799 (-1131T > C), APOE (isoforms) and LPL rs328 (S447X). We found that: (i) genotypes, including those of APOA5 S19W, APOA5 -1131T > C, APOE, GCKR, TRIB1 and TBL2/MLXIPL, were significantly associated with severe HTG; (ii) odds ratios for these genetic variables were significant in both univariate and multivariate regression analyses, irrespective of the presence or absence of diabetes or obesity; (iii) a significant fraction-about one-quarter-of the explained variation in disease status was associated with these genotypes. Therefore, common SNPs (single nucleotide polymorphisms) that are associated with mild TG variation in GWA studies of normolipidemic subjects are also associated with severe HTG. Our findings are consistent with the emerging model of a complex genetic trait. At the extremes of a quantitative trait, such as severe HTG, are found the cumulative contributions of both multiple rare alleles with large genetic effects and common alleles with small effects. Show less

The genetic determinants of severe hypertriglyceridemia (HTG; MIM 144650) in adults are poorly defined. We therefore resequenced 3 candidate genes, namely LPL, APOC2, and APOA5, to search for accumulation of missense mutations in patients with severe HTG compared with normolipidemic subjects. We resequenced >2 million base pairs of genomic DNA from 110 nondiabetic patients with severe HTG and determined the prevalence of coding sequence variants compared with 472 age- and sex-matched normolipidemic controls. We found: (1) heterozygous mutations (LPL p.Q-12E >11X, p.D25H, p.W86R, p.G188E, p.I194T and p.P207L; APOC2 p.K19T and IVS2-30G>A) in 10.0% of severe HTG patients compared with 0.2% of controls (carrier odds ratio [OR] 52, 95% confidence interval [CI] 8.6 to 319); and (2) an association of the APOA5 p.S19W missense variant with severe HTG (carrier OR 5.5 95% CI 3.3 to 9.1). Furthermore, either rare mutations or the APOA5 p.S19W variant were found in 41.8% of HTG subjects compared with 8.9% of controls (carrier OR 7.4, 95% CI 4.5 to 12.0). Also, heterozygotes for rare mutations had a significantly reduced plasma triglyceride response to fibrate monotherapy. Both common and rare DNA variants in candidate genes were found in a substantial proportion of severe HTG patients. The findings underscore the value of candidate gene resequencing to understand the genetic contribution in complex lipoprotein and metabolic disorders. Show less

Common polymorphisms in the promoter of the APOC3 gene have been associated with hypertriglyceridemia and may impact on phenotypic expression of the metabolic syndrome (MetS). The rs7566605 marker, located near the INSIG2 gene, has been found to be associated with obesity, making it also a potential genetic determinant for MetS. The objective of this study is to examine the APOC3 -455T>C and the INSIG2 rs7566605 polymorphisms as potential genetic determinants for MetS in a multi-ethnic sample. Subjects were genotyped for both the APOC3 -455T>C and INSIG2 rs7566605 polymorphisms, and classified for the presence or absence of MetS (NCEP ATP III and IDF definitions). The total study population included 2675 subjects (> or =18 years of age) from six different geographical ancestries. For the overall study population, the prevalence of MetS was 22.6% (NCEP ATP III definition). Carriers of > or =1 copy of APOC3 -455C were more likely to have MetS (NCEP ATP III definition) than noncarriers (carrier odds ratio 1.73, 95% CI 1.40 to 2.14, adjusting for age and study group). The basis of the association was related not only to a higher proportion of -455C carriers meeting the triglyceride and high-density lipoprotein cholesterol criteria, but also the blood pressure criteria compared with wild-type homozygotes. Plasma apo C-III concentrations were not associated with APOC3 -455T>C genotype. The INSIG2 rs7566605 polymorphism was not associated with MetS or measures of obesity. Meta-analysis of the sample of multiple geographic ancestries indicated that the functional -455T>C promoter polymorphism in APOC3 was associated with an approximately 2-fold increased risk of MetS, whereas the INSIG2 rs7566605 polymorphism was not associated with MetS. Show less